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The Bittersweet Promise of Glycobiology

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The Bittersweet Promise of Glycobiology © 2001 Nature Publishing Group http://biotech.nature.com FEATURE The bittersweet promise of glycobiology Carbohydrates play a wide range of important roles in the body and, despite the challenges posed by glycobiology, are now tempting targets for drug developers. Alan Dove Although several genomes have been sequenced and many protein structures Lumen solved, there has been relatively little attention ER Golgi paid, to date, to the various ways in which pro- teins are “tweaked” through the attachment of sugars. However, the process of glycosylation is far from a decorative function. Carbohydrates help determine the three- dimensional structures of proteins, which are inherently linked to their function and their efficacy as therapeutics. Moreover, in contrast Synthesis of Glycan Trimming Further Terminal lipid-linked transfer and trimming glycosylation to some of the other chemical tags employed precursor processing by cells (e.g., phosphates and lipids), carbohy- = glucose = fucose drates exhibit a mind-boggling diversity of = mannose = galactose structures, can confer cell-type specificity, and Cytosol = N-acetylglucose = sialic acid are crucial components of cell-to-cell signal- ing. At the same time, carbohydrates make © Bob Crimi problematic drug targets; they are the most Figure 1. A simplified diagram showing the synthesis of an N-linked glycan. First, sugars are linked difficult biological molecules to analyze and onto a lipid precursor (in the cytosol), which is then flipped over into the lumen of the endoplasmic synthesize, and are rapidly broken down in the reticulum (ER) and the core oligosaccharide finished. The glycan is then transferred to the nascent, growing polypeptide. Sugars are trimmed off, and the polypeptide is then folded (grey oval) before bloodstream. Despite these challenges, recent being moved to the Golgi complex. The glycoprotein goes through a series of further modifications, technological advances have enabled several ending with the capping of the oligosaccharide branches with sialic acid and fucose. Source: biotechnology companies to pursue new car- Helenius, A. & Aebi, M. Science, 291, 2364–2369, 2001. © http://biotech.nature.com Group 2001 Nature Publishing bohydrate-based products, sweetening the outlook for glycobiology. the structures back so that new sugars can can have disastrous consequences. For Carbo loaded be added to a different part of the growing example, in Gaucher’s and Fabry’s diseases, In contrast to DNA, RNA, and proteins, car- carbohydrate structure. The back-and- inherited mutations in carbohydrate-pro- bohydrates can form branching structures, forth process of glycosylation continues cessing enzymes cause glycolipids to accu- and for this reason a relatively simple set of into the Golgi apparatus, which sorts the mulate, leading to damage to the kidneys, sugars can form a huge number of complex new proteins, distributing them to their heart, and brain. The inability to form cer- structures. For example, in theory, the nine final destinations in the cell. In human tain glycoproteins results in another set of common monosaccharides found in cells, sialic acid is usually added to the tips inherited diseases called congenital disor- humans could be assembled into more than of the carbohydrate branches, serving as a ders of glycosylation, which can result in 15 million possible tetrasaccharides, all of final cap important for a variety of glyco- symptoms ranging from chronic diarrhea which would be considered relatively simple protein functions (see Fig. 1). to life-threatening neurological problems. glycans. Different cell types express different Carbohydrates can significantly affect In addition to relatively rare genetic dis- complements of glycosylating enzymes, and protein structure and therefore influence eases, sugars play crucial roles in some have different sets of proteins that can be protein function. Carbohydrates are also leading health problems. Injured tissues glycosylated. Glycosylation is therefore a used as tags to sort proteins in the Golgi stimulate endothelial cells to express flexible evolutionary tool serving a wide apparatus, targeting them to specific com- selectins—glycoproteins that tell leuko- range of purposes in complex organisms. partments within the cell or directing them cytes in the bloodstream to infiltrate dam- The process of glycosylation begins to the cell surface. Once on the cell mem- aged tissue and mount an inflammatory when the protein is targeted to the glycosy- brane, glycoproteins (and glycolipids) response. However, this inflammation lation pathway during translation of mes- interact with receptors on other cells to process can occasionally get out of control. senger RNA (mRNA) into protein. The communicate a wide range of messages. In surviving stroke and heart attack ribosome is attached to the endoplasmic For example, cells of the immune system patients, for example, blood flow is briefly reticulum (ER), and the nascent protein use the glycans on the cells that they cut off from a tissue, then restored. As the fed into the lumen of the ER as translation encounter to identify everything from bac- blood starts to flow again, selectins in the proceeds. In the ER, one set of glycosyla- terial invaders to fellow leukocytes. affected tissue aggressively recruit leuko- tion enzymes attaches sugars to specific cytes from the bloodstream, leading to an portions of the protein. Other glycosyla- Sweet but sickly intense inflammatory response. The result- tion enzymes then either add more sugars Not surprisingly, given the importance of ing tissue damage, so-called reperfusion to these core structures, or partially trim carbohydrates, defects in their metabolism injury, is typically more severe than that http://biotech.nature.com • OCTOBER 2001 • VOLUME 19 • nature biotechnology 913 © 2001 Nature Publishing Group http://biotech.nature.com FEATURE sustained by the initial interruption of of possible carbohydrate structures, and The mixture of carbohydrates can then be blood flow. If the glycan-mediated signal the cumbersome technology available, gly- subjected to high-performance liquid chro- from the selectins could be modulated, the cobiology has been a tough sell for biotech- matography (HPLC) to separate out individ- damage might be mitigated. nology and pharmaceutical companies, ual carbohydrates. Finally, individual carbo- Carbohydrates are also important for made even tougher by a series of high-pro- hydrates can be studied in detail by chemical tumor development because cancer cells file clinical trial failures during the mid- digestion and mass spectrometry, a tech- alter their surface glycoprotein expression 1990s (see below). nique that can give precise structural infor- to evade the immune system. By cloaking mation about relatively small molecules themselves with the right assortment of such as monosaccharides. glycoproteins, the tumor cells can invade I would say that glycoproteomics Besides the complex multistep analysis other tissues without being identified as required for each sugar, glycobiologists aliens. is at least an order of magnitude must also contend with the heterogeneity Sugar structures are also targets for more difficult than proteomics of sugar structures within a sample. For pathogens seeking entry into the cells of example, Pauline Rudd, a scientist at the their host. Because carbohydrates are both Glycobiology Institute at the University of ubiquitous and diverse, viruses and other Oxford (UK), points out that the human intracellular parasites can use glycoprotein Unlike DNA and proteins, no technology prion protein can carry one of 52 different receptors to target any host cell, or just one has been developed to allow carbohydrates sugar structures at one site on the protein: cell type in particular. to be “sequenced” using straightforward “That, of course, makes it very difficult to techniques. Instead, sugar structures must be analyze, because if you’ve got ‘x’ amount No simple solution solved by a combination of chromatography [of sample], you’ve got ‘x’ divided by 52 of For many years, the potential of carbohy- and mass spectrometry, procedures that have any one carbohydrate.” Obtaining suffi- drate-based therapies has been yoked to traditionally required considerable technical cient quantities of a given glycan for analy- seemingly intractable technical problems. skill. “I would say that glycoproteomics is at sis is often a major problem, especially in Without high-throughput methods for least an order of magnitude more difficult studying glycoproteins present in low con- analyzing and synthesizing carbohydrates, than proteomics,” says Anne Dell, a centrations in cells. “We can look at the detailed knowledge of the structure and researcher in the department of biochem- things that are there in very high abun- function of each carbohydrate moiety has istry at the Imperial College of Science, dance, but not at the more interesting been the hard-won products of labor- Technology, and Medicine (London, UK). In things are generally there in low abun- intensive experiments. Indeed, even the a typical experiment, a glycoprotein is isolat- dance,”says Rudd. nomenclature of carbohydrates inhibits ed from a chromatography gel, and the car- Once a carbohydrate structure is solved, easy understanding (see “By any other bohydrate groups are then released from the duplicating the structure artificially can also name”). Given the extraordinary diversity protein by chemical or enzymatic treatment. be a daunting
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